Embryo test could help end HSP

Finding the faulty gene: Embryology test that could kill off inherited illnesses

The development of a universal embryo test that can detect almost any genetic disease is a landmark in medical science’s ability to help couples touched by inherited illness to have healthy children.

While it has been possible since 1989 to screen embryos for certain hereditary conditions, using a technique called preimplantation genetic diagnosis (PGD), its scope has always been limited by technological constraints.

With the fresh approach, known as karyomapping, doctors will be able to offer this service to couples affected even by very rare conditions, on a much faster timescale than is possible at present.

Karyomapping builds on the standard PGD procedure, which was developed by the same doctor, Alan Handyside, in the late 1980s. In PGD, embryos are created by IVF, and when they have grown to eight cells a single cell is removed from each embryo for genetic analysis. Only unaffected embryos are then implanted into the womb.

This can already be done for about 350 genetic conditions, such as cystic fibrosis and Huntington’s disease. Its use is limited, however, because scientists must first identify the precise DNA mutation that affects a family and then develop a test for it. This can take more than a year, and costs several thousand pounds.

A newer version of PGD developed two years ago at Guy’s Hospital in London can screen embryos when precise mutations are unknown, but it still requires lengthy test development.

Karyomapping, by contrast, can be performed within a few weeks, for any inherited condition. At present, costs are comparable to the £1,500(UK) price tag of standard PGD, but these are expected to fall significantly as the technology is developed.

DNA samples are first obtained from the parents and a close relative, usually a child who has the disease in question. This can be done using a noninvasive cheek swab.

This information is then compared with DNA from an embryo, obtained by a biopsy in similar fashion to PGD, to map how its chromosomes are built from the genetic material of its four grandparents. The map can determine whether the embryo has inherited chunks of chromosome that contain any faulty gene.

“What we’re basically doing is mapping family trees, so you can work out which parts of your chromosomes came from which grandparents,” Professor Handyside said. “This turns out to provide a truly universal method for PGD – that’s why we’re excited about it.

“At the moment, there are preimplantation tests for only a small fraction of the 15,000 genetic conditions that are known. This test is capable of detecting any of them. There is no need to find the mutation that is affecting a family, and work up a test. You do the analysis, and just read off the results.”

As the technique maps all the embryo’s chromosomes, it can check any gene, allowing several to be screened at once. It could also be used retrospectively, once an embryo has become a child, to provide wider information about its genetic inheritance.

“At the end of all this, potentially you could give advice to parents about genes linked to things like heart disease in the embryos you’re transferring,” Professor Handyside said. He acknowledged that this raised genetic privacy issues that need to be resolved.

The only kind of genetic conditions that karyomapping cannot detect are those that arise spontaneously, through a random mutation. Even in these cases, it can streamline traditional PGD tests.

Karyomapping can also detect chromosomal abnormalities that often cause embryos to die. It could thus also be used to select embryos with the best chance of developing, enhancing IVF success rates.

The technique could not be used for sex selection for social reasons, which is banned in Britain. Embryos can be screened for sex to prevent diseases that are inherited only by boys.

Professor Handyside will present details of the test next week at a conference in Hinxton, near Cambridge, and at the American Society for Reproductive Medicine’s annual meeting in San Francisco next month. The technique was developed in collaboration with Gary Harton, of the Genetics and IVF Institute in Fairfax, Virginia.

Independent scientists welcomed the development. Dagan Wells, a reproductive geneticist at Oxford University, said: “This is potentially very valuable because the real limitation of PGD is it is time-consuming and expensive. Virtually every patient who comes through the door ends up with a unique test being designed for them. Karyomapping means we can use one platform for almost every single patient and every single disease.”

Anne Child, reader in cardiovascular genetics at St George’s, University of London, said it would help many of her patients with Marfan syndrome, a rare condition that affects the heart. She said: “In the 75 per cent of patients who have other affected family members able to contribute blood samples for study, Professor Handyside’s new approach will be a very welcome addition, permitting the couple to know from the very beginning of the pregnancy that the gene will not be passed on to their children and grandchildren.”

Karyomapping works by analysing chromosomes – the packets that hold genes. Humans have 46 chromosomes arranged into two sets of 23, one provided by the mother and one by the father, through eggs and sperm.

When these are made, they each receive just one set of 23 chromosomes, so that when they fuse they create an embryo with the normal complement of 46.

During this process, a man’s sperm acquires some blocks of DNA that originally came from his mother (the embryo’s grandfather), and some that he inherited from his father (the embryo’s grandfather). The same applies to a woman’s eggs.

Karyomapping involves drawing up a chart of where these grandparental chunks lie on an embryo’s chromosomes. This can be done by comparing DNA from the parents, at least one close relative, and the embryo itself.

Scientists examine more than 300,000 DNA markers throughout the genetic code, which together can show which grandparent provided a particular block of DNA. Once the map is complete, it can be examined for faulty genes.

It is not necessary to know the DNA code of a particular mutation, only its position on a chromosome and the grandparent who passed it on. The gene that causes cystic fibrosis, for example, lies on chromosome 7. If the embryo’s paternal grandfather was a carrier, and the embryo has inherited a chunk of his DNA at the critical position, it will have the faulty gene.

The same thing can be done again and again across all the chromosomes, to allow screening for multiple genes. In practice, this is difficult for more than two or three traits, because few embryos will have the desired DNA at every point. A karyomap could also be reused after a screened embryo has developed into a child. This could reveal genes that give a raised risk of Alzheimer’s or heart disease.

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